ABSTRACT A number of anti-HIV-1 broadly neutralizing antibodies (bNAbs) targeting highly conserved and vulnerable epitope regions of the envelope glycoprotein (Env) are being investigated for a range of clinical applications based on their ability to robustly prevent infection in a variety of animal models. Successful monoclonal antibody (mAb) prophylaxis aims to offer an alternative to vaccine development efforts, and the relatively long half-lives and tolerability profiles of bNAbs promise to offer a complement to the small-molecule inhibitors comprising current pre-exposure prophylaxis (PrEP) options. While bNAbs represent a promising approach to provide protection from infection, suppress plasma and tissue viremia, and reduce viral reservoirs, results from the first major bNAb prevention efficacy trial were mixed. Protection against infection with neutralization susceptible strains was observed, but fewer strains were sufficiently susceptible than anticipated, and overall efficacy criteria were not met. Our objective is to define and refine the means by which bNAbs can be used to restrict HIV replication in vivo using a more stringent model in which their ability to delay or prevent systemic viremia in the context of seeded HIV infection is monitored. We hypothesize that the antiviral activity afforded by a single bNAb can be enhanced by one or more of two distinct strategies that will be rigorously tested for in vivo antiviral activity by benchmarking their ability to delay detectable plasma viremia in the context of spreading infection. Guided by strong preliminary data, the project goals will be achieved though completion of two Specific Aims: 1) Define the ability of Fc engineering to improve bNAb antiviral activity across diverse envelope epitopes, 2) Define the ability of bNAb combinations, with and without Fc engineering to improve bNAb antiviral activity. Each strategy will be evaluated for effects on neutralization and effector function in vitro and in vivo for the ability to delay or prevent systemic viremia. Collectively, these studies will generate unprecedented insights into the means whereby bNAbs, if introduced in early infection after mucosal exposure, delay or restrict viral spread thereby lowering the viral burden and improving outcomes. This work will inform on both next-generation rational vaccine design and the ongoing deployment of bNAb prophylaxis and therapy—driving innovation relevant to combatting HIV acquisition and transmission across diverse intervention strategies and populations.

NARRATIVE The first clinical efficacy trials of a broadly neutralizing antibody (bNAb) resulted in less benefit than expected and suggested that improvements are needed to prevent HIV infection. While considerable effort has focused on optimizing neutralization breadth and potency, it has been unclear what other strategies could also contribute to improving clinical efficacy. Two promising approaches to improve upon the protection afforded by bNAbs are to combine them and to improve their effector functions; defining the extent to which each of these strategies may increase antiviral activity in vivo will contribute to advancement of the most promising strategies to treat and prevent HIV infection.